Nose-to-brain delivery of chitosan coated Leciplex containing zopiclone for improved management of epilepsy: Formulation, pharmacokinetics, and Pharmacodynamics

Abstract

This study focused on designing and optimizing zopiclone-loaded chitosan-coated Leciplex (ZP-CTS-LPX) to improve nose-to-brain delivery for enhanced management of epilepsy. The ZP-CTS-LPX was produced through a one-step manufacturing process, optimized via central composite design to achieve maximum entrapment, zeta potential, and minimal size. The optimized ZP-CTS-LPX underwent in vitro characterization and was subjected to in vivo evaluation studies. The results showed that the ZP-CTS-LPX formulation had a size of 145.40 nm, a surface charge of (+) 62.00 mV, and an entrapment of 68.34 %. The morphological analysis revealed that nanoparticles were spherical and displayed a uniform size distribution, free from aggregation. The research indicated improved ex vivo nasal diffusion, a prolonged release profile, and stability under the tested conditions. ZP-CTS-LPX (IN) demonstrated a relative bioavailability of 269 % in plasma and 690 % in the brain in comparison to ZP-SOL (IN). Furthermore, the ZP-CTS-LPX (IN) demonstrated the highest DTE% (383) and DTP% (73.95) when compared to the ZP-SOL (IN) formulation. Pharmacodynamic assessments showed that the ZP-CTS-LPX group had the longest latency and highest protection percentages against strychnine-induced seizures compared to control and standard treatments. Antioxidant investigations indicated lower oxidative stress and higher glutathione levels in treated groups, while histological analysis confirmed the safety of ZP-CTS-LPX for nasal and brain tissues. These results, coupled with superior pharmacological outcomes and reduced convulsions, demonstrate ZP-CTS-LPX as an effective and safe approach for epilepsy treatment, warranting further clinical evaluation.